The low blood pressure I have on standing, NMH, which is a very consequential problem in my life--I wonder if this is related to lack of acetylcholine?

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I think the biggest problem with NMH is the low blood volume and the excess vasodilation.
Increasing acetylcholine will result in greater sympathetic tone and this sympathetic activation can contribute to hypovolemia and beta receptor mediated vasodilation.
Beside, acetylcholine stimulates nitric oxide mediated vasodilation.
If my hypothesis is correct, higher acetylcholine levels will make you worse unless you suffer from a autonomic neuropathy or a sympathetic neurocirculatory failure.

I don't understand all the terms you used. I do have small fiber neuropathy. I expect I have low blood volume even though I eat lots of salt and I do use compression stockings. When I took Midodrine, which constricts small vessels, the NMH was better, but I suffered too much from coldness and shivering so I stopped that in the fall. I live where it is cold! Then I found out I have the small fiber neuropathy and that this is what is contributing to the numbness, aching, shooting pains and intolerance for most fabrics, etc. Now that it is getting warmer, I think perhaps it would not be wise to take Midodrine again, even though it helped last year--because of the small fiber neuropathy. Maybe those little nerves need whatever blood supply they can get? What I wish is that there were a better treatment for NMH which worked on the brain end of the problem, the lack of signaling to increase BP upon standing!

This study investigated the influence of the cholinergic system on neuro-inflammation using nicotinic and muscarinic receptor agonists and antagonists. Intracerebroventricular (ICV) injection of lipopolysaccharide (LPS, 50 g) was used to induce neuro-inflammation in rats and estimations of pro-inflammatory cytokines, ?7 nicotinic acetylcholine receptor (nAChR) mRNA expression were done in striatum, cerebral cortex, hippocampus and hypothalamus at 24 h after LPS injection. Nicotine (0.2, 0.4 and 0.8 mg/kg, i.p.) or oxotremorine (0.2, 0.4 and 0.8 mg/kg, i.p.) were administered 2 h prior to sacrifice. We found that only nicotine was able to block the proinflammatory cytokines induced by LPS whereas, oxotremorine was found ineffective. Methyllycaconitine (MLA; 1.25, 2.5 and 5 mg/kg, i.p.), an ?7 nAChR antagonist or dihydro-?-erythroidine (DH?E; 1.25, 2.5 and 5 mg/kg, i.p.), an ?4?2 nAChR antagonist, was given 20 min prior to nicotine in LPS-treated rats. Methyllycaconitine antagonized the anti-inflammatory effect of nicotine whereas DH?E showed no effect demonstrating that ?7 nAChR is responsible for attenuation of LPS-induced pro-inflammatory cytokines. This study suggests that the inhibitory role of the central cholinergic system on neuro-inflammation is mediated via ?7 nicotinic acetylcholine receptor and muscarinic receptors are not involved.

Although the aetiology of chronic fatigue syndrome (CFS) is unknown, there have been a number of reports of blood flow abnormalities within the cerebral circulation and systemic blood pressure defects manifesting as orthostatic intolerance. Neither of these phenomena has been explained adequately, but recent reports have linked cerebral hypoperfusion to abnormalities in cholinergic metabolism. Our group has previously reported enhanced skin vasodilatation in response to cumulative doses of transdermally applied acetylcholine (ACh), implying an alteration of peripheral cholinergic function. To investigate this further, we studied the time course of ACh-induced vasodilatation following a single dose of ACh in 30 patients with CFS and 30 age- and gender-matched healthy control subjects. No differences in peak blood flow was seen between patients and controls, but the time taken for the ACh response to recover to baseline was significantly longer in the CFS patients than in control subjects. The time taken to decay to 75% of the peak response in patients and controls was 13.7 +/- 11.3 versus 8.9 +/- 3.7 min (P = 0.03), respectively, and time taken to decay to 50% of the peak response was 24.5 +/- 18.8 versus 15.1 +/- 8.9 min (P = 0.03), respectively. Prolongation of ACh-induced vasodilatation is suggestive of a disturbance to cholinergic pathways, perhaps within the vascular endothelium of patients with CFS, and might be related to some of the unusual vascular symptoms, such as hypotension and orthostatic intolerance, which are characteristic of the condition.

Publication Types: Research Support, Non-U.S. Gov't

PMID: 12950326

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The authors of the study speculate that the prolonged acetylcholine-induced is due to a viral infection. From the full text:

..Speculatively, our findings could be
explained by under-expression of AChE on endothelial cells
(Kirkpatrick et al., 2001): there is evidence that expression of
AChE is inhibited within cholinergically sensitive cells when
infected with herpes simplex virus-type 1 (Rubenstein and
Price, 1984), and that, in the case of lymphocytic choriomen-
ingitis virus, such inhibition of AChE in neuroblastoma cells
persists for years after infection..

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Studies have also found autoantibodies against acetylcholine receptors:

The disturbance of the central nervous system and immunological abnormalities have been suggested in patients with chronic fatigue syndrome (CFS). We focused on immunological abnormalities against neurotransmitter receptors in CFS. Using a sensitive radioligand assay, we examined serum autoantibodies to recombinant human muscarinic cholinergic receptor 1 (CHRM1), mu-opioid receptor (OPRM1), 5-hydroxytryptamine receptor 1A (HTR1A), and dopamine receptor D2 (DRD2) in patients with CFS (n=60) and results were compared with those in patients with autoimmune disease (n=33) and in healthy controls (n=30). The mean anti-CHRM1 antibody index was significantly higher in patients with CFS (p<0.0001) and autoimmune disease (p<0.05) than that in healthy controls, and positive reaction was found in 53.3% of patients with CFS. Anti-OPRM1 antibodies, anti-HTR1A antibodies, and anti-DRD2 antibodies were found in 15.2, 1.7, and 5.0% of patients with CFS, respectively. Anti-nuclear antibodies were found in 56.7% (34/60) of patients with CFS, but anti-nuclear antibody titers did not correlate with the activities of the above four autoantibodies. The patients with positive autoantibodies to CHRM1 had a significantly higher mean score (1.81) of 'feeling of muscle weakness' than negative patients (1.18) among CFS patients (p<0.01). Higher scores on 'painful node', 'forgetfulness', and 'difficulty thinking' were also found in CFS patients with anti-CHRM1 antibodies but did not reach statistical significance. In conclusion, autoantibodies to CHRM1 were detected in a large number of CFS patients and were related to CFS symptoms. Our findings suggested that subgroups of CFS are associated with autoimmune abnormalities of CHRM1.

Publication Types: Research Support, Non-U.S. Gov't

PMID: 12851722 [PubMed - indexed for MEDLINE]

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And here it was found to contribute to orthostatic hypotension/intolerance:

Orthostatic hypotension (OH) is characterized by an abnormal autonomic response to upright posture. Activating autoantibodies to ?1/2-adrenergic (AA?1/2AR) and M2/3 muscarinic receptors (AAM2/3R) produce vasodilative changes in the vasculature that may contribute to OH.
METHODS:

Immunoglobulin (Ig)G from 6 patients with idiopathic OH harboring autoantibodies and from 10 healthy control subjects were examined for: 1) ?1AR and M2R activity with a perfused Purkinje fiber assay and PKA assay in H9c2 cells and 2) vasodilator ?2AR and M3R activity using a pressurized cremaster resistance arteriole assay. Changes in IgG activity with and without propranolol, atropine, and L-NAME were used to estimate AA?AR, AAM2R, and AAM3R activation of their respective functions.
RESULTS:

All six patients had elevated enzyme-linked immunosorbent assay titers to at least one of the receptors compared with controls. ?AR-mediated contractility activity and M2R activity were increased in five of the six patients. IgG from all six patients produced a direct vasodilator effect on cremaster arterioles. ?AR and nitric oxide synthase blockade led to near normalization of IgG-induced vasodilation.
CONCLUSION:

AA?1/2AR and AAM2/3R are present in some patients with idiopathic OH compatible with an in vivo effect. These autoantibodies and their cardiovascular effects provide new mechanistic insights into the pathophysiology of OH.

Copyright 2011 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

PMID:
22130180

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So it looks to me like acetylcholine "toxicity" is involved in CFS, either due to a viral infection or autoimmune antibodies (both?).

I would like to know if the theory of methylation block in CFS still is valid in this scenario? Doesn't methylation increase acetylcholine levels even further? Not trying to bash anyone; simply looking for a solution.

Here is the full abstract of the original study that showed prolonged acetylcholine-induced vasodilatation in CFS:

The authors of the study speculate that the prolonged acetylcholine-induced is due to a viral infection. From the full text:

Studies have also found autoantibodies against acetylcholine receptors:

And here it was found to contribute to orthostatic hypotension/intolerance:

So it looks to me like acetylcholine "toxicity" is involved in CFS, either due to a viral infection or autoimmune antibodies (both?).

I would like to know if the theory of methylation block in CFS still is valid in this scenario? Doesn't methylation increase acetylcholine levels even further? Not trying to bash anyone; simply looking for a solution.

The situation is complicated because several of the neurotransmitters are depleted in ME/CFS. This results, in my opinion, from the partial block in the methylation cycle, which impacts neurotransmitter production and metabolism at several places. I continue to suspect that acetylcholine is low in ME/CFS, for the reasons I have discussed earlier in this thread. I look forward to better measurements of choline in the brain to settle this issue. I think this is going to happen, based on the progress and funding of Dr. Shungu's group.

The situation is complicated because several of the neurotransmitters are depleted in ME/CFS. This results, in my opinion, from the partial block in the methylation cycle, which impacts neurotransmitter production and metabolism at several places. I continue to suspect that acetylcholine is low in ME/CFS, for the reasons I have discussed earlier in this thread. I look forward to better measurements of choline in the brain to settle this issue. I think this is going to happen, based on the progress and funding of Dr. Shungu's group.

Best regards,

Rich

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Ok, thanks. If there is still a theoretical chance of the methylation protocol working, I'm going to try it. I've already tried lower doses of the protocol (in the order of 0.4mg MTHF and 1-2mg B12) for more than 6 months without seeing much change in symptoms, so now I'm trying Freddd's hyperdosing protocol. So far (after increasing to 0.8mg MTHF and 4mg B12) I'm seeing a worsening of symptoms, that seem to be ameliorated by taking extra potassium. I also dumped the NAC I was taking before. We'll see how it goes; thanks for your great work.

Remember that there are two basic types of acetylcholine receptor: the nicotinic acetylcholine receptor, and the muscarinic acetylcholine receptor, so depending on the receptor a cholinergic supplement targets, the effects will be very different.

These two receptor types are distributed in a particular way in the autonomic nervous system (ANS). The distribution is as follows (you can skip this bit and go straight to the "in summary" below):

The ANS has two branches, the sympathetic nervous system, and the parasympathetic nervous system.

Each of these two branches has a preganglionic part (the nerve before it reaches the ganglion), and the postganglionic part (the nerve that continues on from the ganglion and runs to the organ that is controlled by that nerve).

The parasympathetic nervous system uses the neurotransmitter of acetylcholine throughout, but the receptors in the preganglionic part are nicotinic acetylcholine receptors, whereas the receptors in the postganglionic part are muscarinic acetylcholine receptors.

The sympathetic nervous system uses the neurotransmitter of acetylcholine in its preganglionic part (and like the parasympathetic, has nicotinic acetylcholine receptors in the preganglionic part). However the postganglionic part of the sympathetic (mostly) uses a completely different neurotransmitter: noradrenaline, and it therefore uses a completely different receptor there: the adrenergic receptor.

In summary: in the ANS, both sympathetic and parasympathetic use nicotinic acetylcholine receptors;

however, for the most part, it is only the parasympathetic uses muscarinic acetylcholine receptors (so you would target these receptors if you just want to modulate the parasympathetic only);

and only the sympathetic uses adrenergic receptors (so you would target these adrenergic receptors if you just want to modulate the sympathetic).

(In fact, some small parts of sympathetic also use muscarinic acetylcholine receptors: the postganglionic sympathetic nerves that run to the sweat glands uses muscarinic acetylcholine receptors.)

Adrenergic, nicotinic acetylcholine, and muscarinic acetylcholine receptors are all found in the brain too.

The fly agaric mushroom contains muscarine, which activates the muscarinic acetylcholine receptors of the parasympathetic. Though I just read in Wikipedia that muscarine is not the main active component of fly agaric, rather muscimol is and muscimol is potent GABA-A agonist.

However the postganglionic part of the sympathetic (mostly) uses a completely different neurotransmitter: noradrenaline, and it therefore uses a completely different receptor there: the adrenergic receptor.

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This may explain why norepinephrine reuptake inhibitors helped me so much with OI. The autonomic specialist I was seeing believed that many of us with OI have damage to the postganglionic receptors in the sympathetic system.

This may explain why norepinephrine reuptake inhibitors helped me so much with OI. The autonomic specialist I was seeing believed that many of us with OI have damage to the postganglionic receptors in the sympathetic system.

Best,
Sushi

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It may be that autoimmune attack on the adrenergic and/or muscarinic receptors is a major cause of orthostatic intolerance. There was some research that showed lots of CFS patients have autoantibodies to muscarinic receptors. And this new study finds that people with orthostatic hypotension have autoantibodies to both adrenergic and muscarinic receptors.

After re-reading this tread, I came to the conclusion that we are not all the same...
It is necessary to distinguish between the different kinds of dysautonomia groups in ME/CFS.
I think that there are two main groups in ME/CFS: Sympathetic dominance (with a decreased parasympathetic tone) group and a underactive autonomic nervous system group.
I guess that most ME/CFS patients have an increased sympathetic tone and a decreased parasympathetic tone.

Remember that there are two basic types of acetylcholine receptor: the nicotinic acetylcholine receptor, and the muscarinic acetylcholine receptor, so depending on the receptor a cholinergic supplement targets, the effects will be very different.

These two receptor types are distributed in a particular way in the autonomic nervous system (ANS). The distribution is as follows (you can skip this bit and go straight to the "in summary" below):

The ANS has two branches, the sympathetic nervous system, and the parasympathetic nervous system.

Each of these two branches has a preganglionic part (the nerve before it reaches the ganglion "junction box"), and the postganglionic part (the nerve that continues on from the ganglion and runs to the organ that is controlled by that nerve).

The parasympathetic nervous system uses the neurotransmitter of acetylcholine throughout, but the receptors in the preganglionic part are nicotinic acetylcholine receptors, whereas the receptors in the postganglionic part are muscarinic acetylcholine receptors.

The sympathetic nervous system uses the neurotransmitter of acetylcholine in its preganglionic part (and like the parasympathetic, has nicotinic acetylcholine receptors in the preganglionic part). However the postganglionic part of the sympathetic (mostly) uses a completely different neurotransmitter: noradrenaline, and it therefore uses a completely different receptor there: the adrenergic receptor.

In summary: in the ANS, both sympathetic and parasympathetic use nicotinic acetylcholine receptors;

however, for the most part[SUP][/SUP], it is only the parasympathetic uses muscarinic acetylcholine receptors (so you would target these receptors if you just want to modulate the parasympathetic only);

and only the sympathetic uses the neurotransmitter noradrenaline and the corresponding adrenergic receptors (so you would target these adrenergic receptors if you just want to modulate the sympathetic).

(In fact, some small parts of sympathetic also use muscarinic acetylcholine receptors: the postganglionic sympathetic nerves that run to the sweat glands uses muscarinic acetylcholine receptors.)

Adrenergic, nicotinic acetylcholine, and muscarinic acetylcholine receptors are all found in the brain too

The fly agaric mushroom contains muscarine, which activates the muscarinic acetylcholine receptors of the parasympathetic. Though I just read in Wikipedia that muscarine is not the main active component of fly agaric, rather muscimol is and muscimol is potent GABA-A agonist.

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Hip or Jenny, any suggestions for where one might get some of this fly agaric mushroom tincture? I think it might be vauable in my system, given the
symptoms I show. Have either of you, or anyone else here, tried it?

Hip or Jenny, any suggestions for where one might get some of this fly agaric mushroom tincture? I think it might be vauable in my system, given the
symptoms I show. Have either of you, or anyone else here, tried it?

Thanks,

Sing

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Hi Sing

Here is a blog from the person who has been preparing it and taking it. You can email her via the blog. She sent me some - not sure if she has any more though. I tried 2 drops a day so far - not sure if it's doing anything - one day I didn't feel anything, the next I had a very bad spell of tachycardia, sweating and nausea, but that may have been because I had two glasses of wine as well!

Patients with chronic fatigue syndrome experience severe fatigue, orthostatic intolerance and numerous other symptoms that are similar to known illnesses of the autonomic nervous system. Because of these similarities it is possible that disruption of autonomic nervous system nerve transmission may play a role in the symptoms of the illness. In a recent paper, researchers noted that 50% of patients with CFS had antibodies to the muscarinic acetylcholine receptor (Tanaka S, et al. Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome. Int J Mol Med 2003;12:225-230.) The presence of an autoimmune dysautonomia with autoantibodies to the muscarinic acetylcholine receptor is a theoretical etiology for some patients with CFS. If autoimmune dysautonomia exists and can be effectively recognized, therapeutic implications for this group of patients may be developed.

Objective: The present study was designed to examine IgG, IgM, and IgA antibodies to the neuromuscular acetylcholine receptors (AR) and to muscarinic receptors (MR) in patients with chronic fatigue syndrome (CFS) and healthy matched controls.

Methods: Twenty five adults with CFS were matched with healthy community controls for age and sex. After informed consent, venous blood samples were drawn and sent to Immunosciences Laboratory in a blinded manner. The testing procedure was the same as previously described.

Results: Five of the antibodies studies (IgA_AR; IgM_AR; IgG_AR; IgM_MR; and IgG_MR) showed no differences between patients and controls. However the IgA_MR was statistically higher in patients than in controls (0.43 vs. 0.33, p = 0.031).

Conclusions: Our studies are in agreement with the studies of Tanaka et al (1) that autoantibodies against muscarinic receptors may be an important marker in a group of patients with CFS. Further studies should be undertaken to further characterize these autoantibodies and to determine specifics of the subgroup to which they may apply. If this proves to be a consistent finding, therapy directed toward the acetylcholine neurotransmitter system may be of benefit in this group of patients.

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Autoantibodies to muscarinic receptors and beta-adrenergic receptors are also found in orthostatic hypotension:

And in Sjgren's syndrome (dry mouth), which a lot of ME/CFS patients suffer from, signal transmission in the parasympathetic nerves is inhibited by these muscarinic receptor autoantibodies, and this is the likely reason the saliva glands do not get fully activated:

I believe an underactive parasympathetic can also cause circulation problems: cold hand and feet common symptoms in ME/CFS

So if in Sjgren's syndrome, these anti-muscarinic antibodies inhibit signal transmission in the parasympathetic nerves such that the saliva glands remain under activated, then these anti-muscarinic antibodies in ME/CFS patients will presumably be causing body wide inhibition of the parasympathetic nervous system.

I have read some suggestions that the sympathetic/parasympathetic balance may have an impact on the Th1/Th2 immune system balance, so a parasympathetic nervous system inhibited by these anti-muscarinic antibodies may shift the immune response away from Th1 and towards Th2, thus impeding viral clearance.

I sometimes wonder whether these anti-muscarinic antibodies are deliberately triggered by viruses as an immune evasion tactic, as a means to stop the immune system from clearing the virus.

So possibly for ME/CFS patients with anti-muscarinic auto-antibodies, it might be a good idea to take supplements that activate the parasympathetic nervous system; and/or find some medications that can treat this ME/CFS autoimmune condition that targets the muscarinic receptors. Rituximab can treat of autoimmune diseases; perhaps this is one reason why rituximab benefits some ME/CFS patients: because it may help reduce auto-antibodies to muscarinic receptors.

Certainly rituximab can treat Sjgren's, and its anti-muscarinic auto-antibodies:

I believe that the sympathetic/parasympathetic balance has an impact on the Th1/Th2 immune system balance, so a parasympathetic nervous system inhibited by these anti-muscarinic antibodies may shift the immune response away from Th1 and towards Th2, thus impeding viral clearance.

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According to the article below, increased sympathetic tone will suppress Th1 cells, NK cells, macrophages and cytotoxic T cells. So I think you might be right...

So it would seem that for ME/CFS with anti-muscarinic antibodies, it might be a good idea to take supplements that boost the parasympathetic nervous system; or better still, find some medications that can treat this ME/CFS autoimmune condition that targets the muscarinic receptors.

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In my experience, the best way to boost the parasympathetic nervous system is to breath slow and deep.